REVIEW article
Front. Cell Dev. Biol.
Sec. Signaling
Notch signaling in liver diseases: mechanistic insights and therapeutic implications
Qingmiao Shi 1
Na Lou 2
Di Huang 3
Leiya Fu 2
1. The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China
2. First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
3. The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Abstract
The Notch signaling pathway represents an evolutionarily conserved mechanism of intercellular communication that plays critical roles in organ development and tissue homeostasis. However, its functions in liver physiology and pathology demonstrate remarkable context-dependent characteristics, with dysregulated signaling contributing to various liver disorders. This review systematically summarizes the dual and complex roles of Notch signaling in liver health and disease. It comprehensively examines the pathway's essential functions in biliary development, hepatic regeneration, and metabolic homeostasis, while providing a detailed analysis of its pathogenic mechanisms in conditions including Alagille syndrome, drug-induced liver injury, nonalcoholic fatty liver disease, liver fibrosis, hepatocellular carcinoma, and intrahepatic cholangiocarcinoma. Our review particularly emphasizes the dual function of Notch signaling in hepatobiliary malignancies, where it can exert either oncogenic or tumor-suppressive effects depending on specific cellular contexts, molecular interactions, and microenvironmental cuesinfluences. Furthermore, we highlight the evolution of therapeutic strategies from broad-spectrum γ-secretase inhibitors to more precise approaches involving ligand-specific antibodies, transcriptional complex blockers, and pathway agonists, while addressing persistent challenges in clinical translation including on-target toxicities, compensatory resistance mechanisms, and context-dependent responses. Looking forward, this review outlines promising research directions featuring biomarker-guided patient stratification, rational combination therapies with immune checkpoint inhibitors, and spatiotemporally precise regulatoryregulation strategies. By integrating foundational knowledge with recent advances, this work provides valuable insights for understanding Notch signaling's complex roles in liver pathophysiology and for developing novel therapeutic interventions.
Summary
Keywords
liver cancer, Liver Diseases, liver fibrosis, Non-alcoholic fatty liver disease, Notch signaling, treatment strategies
Received
17 December 2025
Accepted
18 February 2026
Copyright
© 2026 Shi, Lou, Huang and Fu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Leiya Fu
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.